: The cellular immune response to HIV has been shown to be robust and continues throughout the natural history of the infection. The capacity for CTL to diminish viral load is substantial, however, sequence variation of HIV limits the effectiveness of the CTL response. Combination pharmacologic therapy against HIV infection known as HAART, has dramatically decreased viral load in many AIDS patients. Despite this control of viral replication, patients who are HAART-responsive for a period of two years or greater, still harbor infectious virus that may, under the appropriate circumstance, become active in replication and cause serious health consequences. The purpose of these studies is to develop immunization strategies in murine models based on immunodominant CTL epitopes from HIV proteins in combination with T-help (HTL) epitopes as part of lipidated peptides. Epitopes will be chosen from sequence-conserved regions of immunogenic HIV proteins. These epitopes will be made into combination vaccines consisting of covalently attached and lipidated HTL+CTL epitopes. The initial approach is to determine the most efficacious means using lipidated vaccines to immunize transgenic mice expressing human HLA Class I and Class II MHC antigens. Mucosal and subcutaneous routes of immunization will be explored. The success of immunization strategies will be evaluated by in vitro methods including the recognition of human antigen presenting cells (APC) which will be infected with different isolates of HIV. The choice of CTL epitope will be made using the criteria that the recognition should be restricted by common HLA Class I alleles. One of the main goals of the proposal and the Innovation Grant Program is to evaluate means to propagate the CTL response using strong T-help (HTL) epitopes. The applicants will evaluate a series of HTL epitopes in combination with selected CTL epitopes using immunization strategies detailed in the proposal. The efficacy of the immune strategies will be examined further using a mouse model of HIV infection referred to as the huPBL-SCID mouse. Immunodeficient mice will be repopulated with human PBL of known HLA type and infected with various isolates of HIV. Vaccine stimulated CTL obtained from transgenic mice will be infused in the previously HIV infected huPBL SCID mice to evaluate their potential for recognition/lysis of infected cells and reduction of viral load. The vaccine strategy that results in the most successful reduction in viral load should be considered in terms of future human immunization clinical protocols for patients on HAART during the time when viral replication is suppressed.